We know defects in this cellular pathway cause genetic diseases that lead to bleeding problems or skeletal defects in humans, said Simeon Boyadjiev Boyd, chief of the Section of Genetics with UC Davis Childrens Hospital and lead author of the UC Davis study. But this is the first time these defects have been linked to craniofacial abnormalities. Although cranio-lenticulo-sutural dysplasia is rare, this new finding opens up the intriguing possibility that more skeletal and connective tissue disorders are also caused by mutations in the pathway.

By UC Davis Health System, [RxPG] A research team led by a UC Davis Childrens Hospital scientist has identified a genetic mutation as the cause of a congenital craniofacial birth defect called cranio-lenticulo-sutural dysplasia. The mutation closes off a pathway that is vital to the transport of cellular proteins and, in doing so, significantly alters normal growth patterns of skeletal and connective tissue. The research finding, which appears in the October issue of Nature Genetics (http://press.nature.com), is independently confirmed in a Vanderbilt University Medical Center study published in the same issue.

We know defects in this cellular pathway cause genetic diseases that lead to bleeding problems or skeletal defects in humans, said Simeon Boyadjiev Boyd, chief of the Section of Genetics with UC Davis Childrens Hospital and lead author of the UC Davis study. But this is the first time these defects have been linked to craniofacial abnormalities. Although cranio-lenticulo-sutural dysplasia is rare, this new finding opens up the intriguing possibility that more skeletal and connective tissue disorders are also caused by mutations in the pathway.

Congenital birth defects of the face and skull are relatively common and are estimated to affect one in every 500 to 1,000 babies born in the United States. Boyd and colleagues first identified cranio-lenticulo-sutural dysplasia in a consanguinous Saudi Arabian family in 2003. Affected children inherit the defective gene from both parents and can have skull bones that take an abnormally long time  sometimes well into teenage years  to completely close. As a result, the childrens heads are very wide at the top and almost pointed in the chin region. They can also have scoliosis, eye cataracts, unusually wide set eyes and developmental delays.

After identifying the disorder, Boyd, who was then at the Johns Hopkins University School of Medicine, set about finding the cause. Using genetic linkage analysis, he and his research team were able to map the defect to a particular region of human chromosome 14 and find the exact mutation in gene SEC23A. They learned that the mutation inactivated the SEC23A protein, an integral component of a critical intracellular pathway  called the COPII-mediated secretory pathway  that moves proteins from one part of a cell to another. To create healthy tissue and bones, certain proteins must move through this secretory pathway. For individuals with cranio-lenticulo-sutural dysplasia, this transition is impossible. As a result, the proteins accumulate and enlarge one part of the cell called the endoplasmic reticulum, which was confirmed for this study using electron microscopy and immunofluorescence.

In the Vanderbilt study, Lang, et. al., describes a similar mutation in the SEC23A gene that causes defects in zebrafish, including a malformed craniofacial skeleton, kinked pectoral fins and a short body length. Other studies have found that SEC23A mutations cause cellular defects in lower organisms. Boyd predicts that other human diseases resulting from mutations in the transport system are likely to be discovered.

People with these defects live well into adulthood but, because of the redundancy of systems in the body, they may have a series of medical problems involving multiple organs, the face, the brain and the skeletal system. They bounce from doctor to doctor, each of whom treats a particular concern such as cataracts, skeletal defect or mental retardation, but nobody knows why those patients have breakage of multiple systems, he said. Our goals now are to identify these disorders using a reverse genetic approach and knock-out gene studies and to explore if the specific cellular changes can be used to screen for other disorders in the secretory pathway.

Boyds research may also have implications in the areas of aging, neurodegeneration and endocrinology, since cell function decline and damage of the endoplasmic reticulum occur with age and could play a role in Alzheimers and Parkinsons diseases.

We also expect that the disorders in this particular part of the secretory pathway will manifest with endocrine problems, such as diabetes. Most hormones, including insulin, are secretory proteins that must be processed in the endoplasmic reticulum and exported elsewhere, he said.

Boyds research team included Lelio Orci from the University of Geneva, Switzerland, a recognized leader on cell morphology; Randy Schekman and Chris Fromme from the University of California, Berkeley, who used biochemical characterization of the mutant cells to precisely pinpoint the mechanism leading to cranio-lenticulo-sutural dysplasia; and Samuel Chong from University of Singapore, who inactivated the corresponding gene in zebrafish and was able to produce very similar skeletal defects.

This project is especially rewarding as it demonstrates how collaboration between scientists with similar interests but different expertise can rapidly advance the field, said Boyd.

The study was supported with grants from the National Institute of Dental and Craniofacial Research  National Institutes of Health, the Swiss National Science Foundation, the Miller Institute for Basic Research, the Howard Hughes Medical Institute and the National University of Singapore.

UC Davis Childrens Hospital is the Sacramento regions only comprehensive hospital for children. From primary care offices to specialty and intensive care clinics, pediatric experts provide compassionate care to more than 74,000 children each year and conduct research on causes and improved treatments for conditions such as autism, asthma, obesity, cancer and birth defects.

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